Recently, the treatment through administration of insulin preparations has been performed mainly for patients with severe diabetes. Various insulin preparations aiming at improving the patients' QOL, such as quick-acting or sustained-release subcutaneous preparations, inhalers, oral preparations and the like have been developed, but they are by far inferior to the physiologic function of the pancreatic beta cells that act to accomplish automatic or autonomic fine adjustment according as the blood sugar level varies. Additionally, the long-term administration results in eventual onset of complications of diabetes (microangiopathy and large-vessel disorders), which constitute a major risk factor for arteriosclerosis.
Insulin is the most important blood-sugar regulating hormone in animals and its production or generation and secretion are locally limited to the pancreatic beta cells. Therefore, the research and development work, which is currently under way on the diabetic drugs, includes (1) the research on the development, differentiation, apoptosis and regeneration of the pancreatic beta cells, (2) the research on the insulin secretion mechanism, (3) the research on deficiency of the action of insulin and the like.
The pancreatic beta cells, though they were once considered non-proliferative, continue to undergo new regeneration from their precursor cells to form the islet cells even after birth, according as various environmental factors change. In addition, the differentiated pancreatic beta cells are known to proliferate but at a low rate. On the other hand, part of the pancreatic beta cells is lost by apoptosis and turns over every 40 to 50 days. In these manners, it has been clarified that the amount or quantity of the pancreatic beta cells gently increases throughout their lives.
Insulin resistance develops by damages to the cells, as well as pregnancy, obesity and the like, and in the case of an increased requirement of insulin secretion, new beta cells regenerate from their precursor cells being accompanied by beta cell hypertrophy. As a result, the amount or quantity of the beta cells increases, and normal sugar metabolism is maintained.
Insulin secretagogues represented by sulfonylurea drug agents, on the other hand, exhaust the pancreatic beta cells eventually.
Referring to an approach from the standpoint of regenerative medicine, enhanced attention as a novel remedy for diabetes is being drawn to a method which involves activating in vivo the differentiation-inducing system of endogenous precursor (stem) cells of the pancreatic beta cells to thereby promote proliferation of the pancreatic beta cells for enhancement of their function. From the research study on the human embryonic pancreatic cells utilized for the differentiation/proliferation and function-enhancement actions for the pancreatic beta cells, notice has also been attracted to the cytokines of various growth factors, such as HGF (hepatocyte growth factor) and the like, and many reports have recently been published. In addition, attention is being directed to the remedy concerning the management of glucagon-like peptide-1 (hereinafter abbreviated as GLP-1) and gastric inhibitory peptide (hereinafter abbreviated as GIP), which are the gastrointestinal hormones possessing the same action.
GLP-1 and GIP, belonging to a group of gut-derived hormones called incretins, are the peptides that are profoundly involved in the adjustment or regulation of the glucose homeostasis. GLP-1 is synthesized in gut L cells through tissue-specific posttranslational processing of a preproglucagon, or a glucagon precursor, and is released into the circulation in response to a diet. These peptides are major mediators of the enteroinsular axis and bind to specific receptors to exert their actions.
GLP-1 acts mainly on the pancreas and is known to promote the insulin release by pancreatic beta cells in a glucose-concentration dependent manner. Additionally, GLP-1 inhibits glucagon secretion and delays emptying of stomach, and there is suggested a possibility that it would augment peripheral glucose disposal through metabolism.
From the fact that postcibal glucose levels are normalized in patients with noninsulin-dependent diabetes mellitus by administration of GLP-1, the possibility is suggested that GLP-1 could be used as a therapeutic drug for diabetes mellitus (refer to Diabetes care, 17(9), pp. 1039-1044, (1994)). Also, GLP-1 displays the blood-sugar controlling action in patients with insulin-dependent diabetes mellitus (refer to Diabetes Care, 19(6), pp. 580-586, (1996)). Since the insulin-release promoting action of GLP-1 depends on the plasma glucose levels (refer to Nature, 361, pp. 362-265, (1993)), furthermore, the insulin release mediated by GLP-1 is reduced at lowered plasma glucose levels, thereby offering the advantages that severe hypoglycemia is not induced and that body weight gain is not promoted. Consequently, diabetes treatment with an enhanced degree of safety can be considered feasible by controlling the blood GLP-1 levels, as the case may be.
As a procedure of controlling the plasma GLP-1 levels, it is possible to administer to patients GLP-1 itself or modified GLP-1, but activated GLP-1 (GLP-1[7-36]amide), which shows a very short plasma half-life of about 1 to 6 minutes and turns into inactivated GLP-1 (GLP-1[9-36]amide) (refer to Endocrinology, 136, pp. 3585-3596, (1995)), can offer the limited possibility as a therapeutic agent. As a stable modified GLP-1 agonist, in addition, exendin-4 and others have been developed, but these are required to be injected twice a day, while their side effects, such as emesis, have been reported.
Furthermore, the inactivation of activated GLP-1 by dipeptidyl-peptidase IV (hereinafter referred to briefly as DPP-IV) is known as a mechanism for controlling the plasma GLP-1 level. Accordingly, it is possible to maintain the required amount of activated GLP-1 in blood by inhibiting DPP-IV (refer to Diabetologia, 42, pp. 1324-1331, (1999)), and Diabetes 47, pp. 1663-1670, (1998)).
Also, there have been published the compounds that generate or induce the secretion of GLP-1 (refer to WO99/08991, 41st Annual Meeting of the Japan Diabetes Society, No. 3N 004, (1998), and 43rd Annual Meeting of the Japan Diabetes Society, No. I-5-12 (2000)).
The protease-inhibiting compounds, as described in JP-A 52-89640, have been demonstrated to inhibit onset of diabetes-like symptoms in diabetes animal models, and have also been reported to exhibit suppression of fasting blood sugar levels, retention or maintenance of pancreatic insulin generation or secretion, and suppression of plasma glucagon amount and glucagon content (refer to Journal of the Japan Diabetes Society, 24(1), pp. 77-79, (1981), Journal of the Japan Diabetes Society, 27(10), pp. 1083-1093, (1984), Endocrine Journal (the Japan Endocrine Society) 60(5), pp. 684-695, (1984), and Pancreas 8(2), pp. 196-203, (1993)). In addition, said compounds have been proven to promote significant decreases in blood sugar levels and also eventual reduction of insulin requirements in patients with noninsulin-dependent diabetes mellitus, while the possibility of ameliorating abnormal glucagon secretion is suggested (refer to New Horizon for Medicine, 21, pp. 2806-2810, (1989)).
Meanwhile, the protease-inhibiting compounds according to the present invention are described in JP-A H08-109164, JP-A H07-206801, JP-A H08-143529, JP-A S61-33173 and Biochemica Biophysica Acta, 661(2), pp. 342 (1981), however, it is not suggested that these compounds exhibit such actions as suppression of fasting blood sugar levels, retention or maintenance of pancreatic insulin generation or secretion, suppression of plasma glucagon amounts, promotion of GLP-1 increases and inhibition of complications of diabetes and the like.